Method of forming glyoxylic acid semicarbazone

ABSTRACT

A method of forming glyoxylic acid semicarbozone by reacting a cyanate with a neutralized hydrazine solution for a period of time, followed by either addition of glyoxylic acid or adjusting the pH and adding chloral whereby a solid semicarbazone product is precipitated.

United States Patent I191 Deutsch 1 Jan. 7, 1975 METHOD OF FORMING GLYOXYLIC ACID SEMI-CARBAZONE [52] LES. Cl. 260/534 R, 260/554 [51] Int. Cl C07c 133/04 [58] Field of Search 260/534 R, 554

[56] References Cited UNITED STATES PATENTS 2,779,786 1/1957 Coleman et a] 260/534 R 3,427,306 2/1969 Portelli 260/534 R Primary Examiner-Vivian Garner [57] ABSTRACT A method of forming glyoxylic acid semicarbozone by reacting a cyanate with a neutralized hydrazine solution for a period of time, followed by either addition of glyoxylic acid or adjusting the pH and adding chloral whereby a solid semicarbazone product is precipitatedi 8 Claims, N0 Drawings METHOD OF FORMING GLYOXYLlC ACID SEMl-CARBAZONE in the prior art for formulating the starting 6 azauracil.

Perhaps the most effective process for forming 6- azauracil comprises the cyclization of glyoxylic acid semicarbazone. Thus, this semicarbazone is a valuable starting material in the synthesis of 6-azauracil which in turn is utilized to form valuable drug products through additional reactions.

One obvious method of forming glyoxylic acid semicarbazone involves. the reaction of glyoxylic acid and semicarbazide. Glyoxylic acid is relatively expensive and thus the cost of the desired semicarbazone is quite expensive. Another reported method for forming a semicarbazone is by heating chloral and semicarbazide hydrochloride in an aqueous solution. Once again, in this instance, the semicarbazide hydrochloride is an expensive starting material and thus serves to add sub stantially to the cost of the semicarbazone to be formed. It should be apparent that if the semicarbazone is expensive as a starting material for forming the 6- azauracil then the price of the resulting products, or drugs produced, will reflect same. A reduction in the cost of any intermediate or starting material in the formation of such products is valuable in making the resulting item more economically feasible.

Briefly, the herein invention comprises a new method forpreparing glyoxylic acid semicarbazone utilizing inexpensive ingredients such that the resulting semicarbazone will have a reduced price as compared to that manufactured in prior art technique. In accord with the herein process, potassium cyanate is reacted with a neutralized hydrazine solution for a period of several hours. The solution is then reacted with either glyoxylic acid or chloral. When chloral is used, the pH of the solution is adjusted prior to addition of the chloral. In both instances, a precipitate of the semicarbazone is formed from the reactions. It is believed that the invention will be further understood from the following description and examples.

To form the glyoxylic acid semicarbazone, a neutral aqueous solution of hydrazine is first prepared. The amount of hydrazine in the solution can range from I to 30 weight percent. It is generally preferred that the solution contain about 10 percent hydrazine. Added to the neutral hydrazine solution is a cyanate. Preferably, potassium cyanate is utilized. Other alkali metal cyanates are somewhat unstable in water, particularly potassium cyanate, it is desirable to have a small excess over that stoichiometrically required for the reaction involved. Thus, it is preferable to 'have from 5-25 weight percent excess of the cyanate. The third additional ingredient initially added to the reaction is an acid. Though hydrochloric acid is preferred, other mineral acids, such as sulfuric and phosphoric acids can be utilized. Additionally, weak acids are contemplated such as acetic and formic acid, though they are not as preferred. The acid could be any convenient strength or concentration. However, there must be at least one mole equivalent of acid for each mole of cyanate utilized, as can bereadily apparent from the following equation between the three reactants to form the semicarbazide.

The above reaction 1 forms, as can be seen, an intermediate semicarbazide in solution. As will be seen, one of the advantages of the herein invention is to utilize a solution of the semicarbazide formed in reaction 1 above without the need for isolating the semicarbazide prior to forming the desired product. The above reac- 2 tion to form the intermediate semicarbazide can be carried out from 4 to 24 hours at room temperature. It has generally been found that 'the reaction is completed in eight hours. The completion of the reaction is dependent on temperature, time and concentration of reactants. The time of reaction can be reduce significantly by raising the temperature of the reaction to within the range of 50 to C, but reaction temperatures between 10 and C may be used.

The solution formed in reaction labove can then be utilized in one of two ways, in accord with the herein invention. In a first approach, glyoxylic acid is added tothe mixture in an amount to stoichiometrically react with the semicarbazide. Once the acid is dissolved in solution, a new precipitate starts to form almost at once. The reaction is complete when no more precipitate forms which is in the range of from 15 minutes to 2 hours. The precipitate which crystallizes out, is the desired glyoxylic acid semicarbazone. The temperature of the reaction with the glyoxylic acid can vary from room temperature to near the boiling point of water. After the reaction, the mixture'should be cooled to at least room temperature to ensure a good yield. The reaction with the glyoxylic acid to form the desired semicarbazone is seen from reaction 2 below.

The second approach utilizing the solution formed in reaction 1 above, eliminates the requirement for glyoxylic acid which is a relatively expensive ingredient. In this method, the solution of the intermediate semicarbazide of reaction 1 is treated with further acid to bring the pH within the range of 5 to 7. This step of acid addition is preferred in order to assure that the further reaction required to form the desired semicarbazone will achieve a good yield of a pure material. The acidified solution is preferably cooled to room temperature before the next step which is extremely exothermic. After cooling to room temperature, chloral is then added in a stoichiometric amount equivalent to semicarbazide present.

The mixture is then stirred as it is initially in two phases, and heated'with a bath set in a range of 7090 C EXAMPLE 1 Into a 125ml. Erlenmeyer flask was placed 2.9 mls. of 54.4% aqueous hydrazine solution, 50 mls. of water, 4.2 mls. of 12 N hydrocholoric acid, and last, 4.9 gms. of practical grade potassium cyanate. A'clear solution was obtained. The solution was allowed to stand at room temperature for 1 4 hours, and then 46 gms. of glyoxylic acid monohydrate was added. The acid quickly dissolved and a new precipitate started forming almost at once. After standing for 30 minutes, the precipitate was collected and washed with approximately 60 mls. of water. The solid was air dried to yield'5.0 gms. of white product which was glyoxylic acid semicarbazone.

The melting point of the product was 207209 C compared with 207209 C for a known sample. Thin layer chromatography using Silufol UV 254 ascending in Butanol: Acetic Acid: Water, 812:2 gave a single spot indistinguishable from a known sample and with an R,

EXAMPLE Il utes and a precipitate started forming. After atotal of 28 minutes, the reaction mixture was cooled in an ice bath for 20 minutes and then the precipitatewas collected, washed with cold water, methanol and air dried. Yield, 7.0 gms. of first-crop material. A second crop,

0.6 gms. formed in the mother liquors on standing overnight.

The main cro'p had a melting point of 205-207 C compared to 207209 for a standard sample. Thin layer chromatography using Silufol UV 254. ascending in ButanolzAcetic Acid:Water, 8:2:2 gave a single spot of R, 0.60 indistinguishable from that of a known sample.

I claim: l. A method of forming glyoxylic acid semicarbazone comprising:

mixing an alkali metal cyanate, an aqueous neutral hydrazine solution having a concentration of hydrazine of from 1 to 30 weight per cent,said cyanate being present in an amount of about 5 to 25 weight percent excess of an equal molar amount of said hydrazine and at least one mole of an acid for each mole of said cyanate, reacting the mixture atfrom 10 to 80 C to form an intermediate semicarbazide in solution,

adding an acid to said intermediate semicarbazide solution in an amount sufficient to bring the pH within the range of 5 to 7, and heating the mixture at from 70-90 C., under reflux conditions after the chloral has been added.

2. The method of claim 1 further including the step of cooling said heated mixture after about 30 minutes of heating. I

3. The method of claim 2 whereinsaid cooling is to below room temperature and the reaction mixture maintained in a cooled condition for at least about 30 minutes. 7 t

4. The method of claim 1 wherein said cyanate is potassium cyanate.

5. The method ofclaim 1 wherein said aqueous neutral hydrazine solution has a concentration of about 10 per cent by weight hydrazine. g

6. The method of claim 1 wherein said cyanate and hydrazine are reacted at a temperature of from about 50 C to about 70 C.

chloric acid. 

1. A METHOD OF FORMING GLYOXLIC ACID SEMICARBAZONE COMPRISING: MIXING AN ALKALI METAL CYANATE, AN AQUEOUS NEUTRAL HYDRAZINE SOLUTION HAVING CONCENTRATION OF HYDRAZINE OF FROM 1 TO 30 WEIGHT PER CENT, SAID CYANATE BEING PRESENT IN AN AMOUNT OF ABOUT 5 TO 25 WEIGHT PER CENT EXCESS OF AN EQUAL MOLAR AMOUNT OF SAID HYDRAZINE AND AT LEAST ONE MOLE OF AN ACID FOR EACH MOLE OF SAID CYANATE, REACTING THE MIXTURE AT FROM 10* TO 80*C TO FORM AN INTERMEDIATE SEMICARBAZIDE IN SOLUTION, ADDING AN ACID TO SAID INTERMEDIATE SEMICARBAZIDE SOLUTION IN AN AMOUNT SUFFICIENT TO BRING THE PH WITHIN THE RANGE OF 5 TO 7, AND HEATING THE MIXTURE AT FROM 70*-90*C., UNDER REFLUX CONDITIONS AFTER THE CHLORAL HAS BEEN ADDED.
 2. The method of claim 1 further including the step of cooling said heated mixture after about 30 minutes of heating.
 3. The method of claim 2 wherein said cooling is to below room temperature and the reaction mixture maintained in a cooled condition for at least about 30 minutes.
 4. The method of claim 1 wherein said cyanate is potassium cyanate.
 5. The method of claim 1 wherein said aqueous neutral hydrazine solution has a concentration of about 10 per cent by weight hydrazine.
 6. The method of claim 1 wherein said cyanate and hydrazine are reacted at a temperature of from about 50* C to about 70* C.
 7. The method of claim 1 wherein said acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid.
 8. The method of claim 7 wherein said acid is hydrochloric acid. 